A novel lead of P-selectin inhibitor: Discovery, synthesis, bioassays and action mechanism

Jianhui Wu; Ming Zhao; Yuji Wang; Yaonan Wang; Haimei Zhu; Shurui Zhao; Shiqi Peng

doi:10.1016/j.bmcl.2016.08.061

A novel lead of P-selectin inhibitor: Discovery, synthesis, bioassays and action mechanism

Bioorg Med Chem Lett. 2016 Oct 1;26(19):4631-4636. doi: 10.1016/j.bmcl.2016.08.061. Epub 2016 Aug 21.

Authors

Jianhui Wu¹, Ming Zhao², Yuji Wang¹, Yaonan Wang¹, Haimei Zhu¹, Shurui Zhao¹, Shiqi Peng³

Affiliations

¹ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China.
² Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: mingzhao@bjmu.edu.cn.
³ Beijing Area Major Laboratory of Peptide and Small Molecular Drugs, Engineering Research Center of Endogenous Prophylactic of Ministry of Education of China, Beijing Laboratory of Biomedical Materials, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, PR China. Electronic address: sqpeng@bjmu.edu.cn.

PMID: 27575475
DOI: 10.1016/j.bmcl.2016.08.061

Abstract

By docking 126 derivatives of β-carboline-3-carboxylic acid, tetrahydro-β-carboline-3-carboxylic acid and indoloquinolizine into the active pocket of P-selectin (2-(3-(hydroxymethyl)-9H-pyrido[3,4-b]indol-1-yl)ethyl)-l-phenylalanine (HMCEF) was assigned a novel inhibitor. ELISA and flow cytometry experiments showed that HMCEF effectively down-regulated P-selectin expression and supported the rationality of the computer assistant screening, while UV spectrum experiments demonstrated that HMCEF directly bound to P-selectin. In vivo HMCEF dose dependently inhibited the rats and mice to form thrombus and had a minimal effective dose of 20nmol/kg, dose dependently inhibited inflammatory response of mice and had a minimal effective dose of 20nmol/kg. The decrease of serum TNFα and IL-8 of the treated mice was proposed to be the action mechanism of HMCEF inhibiting thrombosis and inflammation. All data imply that HMCEF is a novel lead of P-selectin inhibitor.

Keywords: Anti-inflammation; Anti-thrombosis; Inhibitor; P-selectin; β-Carboline.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dose-Response Relationship, Drug
Drug Discovery
Enzyme-Linked Immunosorbent Assay
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Mice
P-Selectin / antagonists & inhibitors*
Phenylalanine / analogs & derivatives*
Phenylalanine / chemical synthesis
Phenylalanine / chemistry
Phenylalanine / pharmacology
Rats
Spectrophotometry, Ultraviolet

Substances

2-(3-(hydroxymethyl)-9H-pyrido(3,4-b)indol-1-yl)ethyl)-l-phenylalanine
Indoles
P-Selectin
Phenylalanine